Little is known about the ability of the brain to repair traumatic brain injury (TBI). Drugs have been developed that treat TBI by preventing injury, but to date these drugs have failed clinical trials. As a result, there are no treatments available to the 1.7 million Americans who annually sustain TBI. Recently, however, the FDA-approved drugs, minocycline plus N-acetyl cysteine, have been shown to improve cognition and memory after experimental TBI. The mechanism of how these drugs work is unknown. These observations provide the justification for the long-term goal to improve brain function by repairing, rather than preventing, TBI. This proposal will test a central hypothesis that: Minocycline (MINO) and N-acetyl cysteine (NAC) promote remyelination and improve cognition and memory following TBI. Three specific aims will test this hypothesis: 1) When and where does MINO plus NAC induce remyelination in the controlled cortical impact (CCI) model of TBI? Preliminary data show that CCI produces widespread demyelination of midline white matter structures, and MINO plus NAC has little effect on this demyelination. Within 2 weeks, MINO plus NAC treatment increased myelin content in previously demyelinated white matter tracts. 2) Which cell types are modulated by MINO plus NAC? Preliminary data indicate that MINO plus NAC modulate microglial polarity in injured white matter by increasing the numbers of anti-inflammatory, tissue-remodeling M2 microglia while decreasing pro-inflammatory M1 microglia. MINO plus NAC also induce oligodendrocytes to increase myelin content in demyelinated white matter. 3) Does remyelination improve cognition and memory? Preliminary data show that CCI prevents acquisition and long-term retention of an active place avoidance task. Both acquisition and retention are improved by MINO plus NAC treatment. Preliminary data also show that an unilateral stereotaxic injection of lysophosphotidylcholine (LPC) into the fimbria produces a localized demyelination and cognitive deficits similar to CCI. Unlike CCI, the LPC-demyelinated fimbria spontaneously remyelinates. Remyelination of the fimbria is accompanied by reversal of the cognition deficits produced by demyelination. This proposed research is both innovative and significant because it explores the novel finding that the ability to remyelinate is not lost following TBI and can be restored with drugs. If successful, the proposed experiments will substantively increase our knowledge of the pathophysiology of TBI as well as provide important information on the drug action of MINO and NAC. The safety and efficacy of MINO and NAC are well-established because both drugs are FDA-approved for uses other than TBI and are in clinical trials, as single drugs, for a variety of brain diseases. The re-use of FDA-approved drugs is perhaps the fastest route to get new drugs to treat TBI into clinical trials. Ultimately, the knowledge gained from this proposal has the potential to greatly improve quality of life after traumatic brain injury.